The human immune system is a potentially powerful line of defense against cancer. Many biological obstacles exist in cancer patients that can thwart tumor specific immune responses. While there is compelling evidence that the immune system is capable of generating highly effective antitumor responses, the vast majority of immunotherapeutic interventions show only modest clinical impact. The opportunity to train the immune system to efficiently recognize and kill tumor cells could be highly significant because of the generation of immunologic memory induced by vaccination. The hypothesis in this application is that the design of unique B cell epitope peptides which can recapitulate the exquisite native structure of the tumor antigen and when combined with a "promiscuous" T cell activating species results in the production of highly efficacious native-like antipeptide antibodies. We have demonstrated in preclinical studies that such endogenous antibodies can delay, prevent and/or eradicate tumor growth and metastasis with increased efficacy and little or no toxicity. Thus, the overall goal of this project is to continue to test this hypothesis in humans by attempting to control or cure metastatic cancers. Human epidermal growth factor receptor (HER) signaling inhibition plays a major role in targeted cancer therapies. HER-2 over expression and amplification is seen in subsets of breast, gastric, esophageal, endometrial, uterine, ovarian, and lung cancers. HER-2 plays a major coordinating role in this network of family of HER receptors (EGFR (HER-1), HER-2, HER-3, and HER-4). To achieve our objectives two aims are proposed: Specific Aim 1: To perform early phase clinical trial assessing safety and clinical toxicity of immunization, as well as to establish an optimum biologically dose (OBD) of combination vaccines. Specific Aim 2: To determine whether both humoral and cellular immune responses are elicited in patients immunized with combination vaccines and nor-MDP as adjuvant and to study the underlying mechanisms of anti-tumor activity in vitro and in vivo. Correlative studies that include state of the art immunological monitoring, in vitro mechanism of action. In this project basic and clinical science will be conducted in parallel, each informing the other;basic scientists and physician-scientists will work together as a team to develop discovery-based science that will change the care of patients. PUBLIC HEALTH RELEVANCE: The proposed clinical trial and research program has as its goal to define the basic knowledge required for engineering the human immune system to recognize and destroy deadly forms of cancer. Both preclinical animal and human clinical studies with a HER-2 peptide vaccine point to the possibility of controlling cancer. This project will be to continue to determine whether better peptide vaccines can be engineered to produce cancer-killing antibodies with high efficacy. Scientific advances from this project will have a significant public health impact for cancer. The advantage of active immunotherapy with safe and non toxic natural synthetic peptides over passive immunotherapy with mAbs such as trastuzumab (Herceptin) is a fundamental aspect of this work.